IL-22RA (also known as IL22R, IL22R1, IL22RA1, CRF2-9 and Zcytor11) belongs to the type II cytokine receptor family and is a component of the receptor for IL-20, IL-22 and IL-24. Due to their structural similarity IL-20, IL-22 and IL-24, together with IL-19 and IL-26, were combined with IL-10 in the so-called “IL-10 family” (Kunz S et al. 2006). IL-10 is a master regulator of the immune response that mediates down-regulation of pro-inflammatory cytokine expression in macrophages, T cells, and other cells of the immune system (Moore K W et al. 2001).
In vitro, IL-20 and IL-24 are produced not only by activated immune cells, but also to a similar extent by keratinocytes. In vivo, these cytokines are expressed preferentially in the inflamed tissues. IL-20 and IL-24 can signal through two receptor complexes, IL-20RA/IL-20RB and IL-22RA/IL-20RB (Langer J A et al. 2004). Several tissues, particularly the skin, tissues from the reproductive and respiratory systems, and various glands appeared to be the main targets of these mediators (Kunz S et al. 2006).
IL-22 was discovered as a gene up-regulated by CD4+ T cells upon activation and it shares 22% amino acid sequence identity with IL-10; it was, thus, originally named IL-10-related T cell-derived inducible factor (IL-TIF) (Dumoutier L et al. 2000). Unlike IL-10, which regulates immune cell functions, IL-22 controls tissue responses to the immune system. IL-22 signals through a heterodimer receptor formed by IL-22RA and IL-10RB which is highly expressed within various tissues but it is not detectable on immune cells. Initially, IL-22 binds via its IL-22RA binding site to the extracellular domain of IL-22RA and, subsequently, IL-10RB binds to a region created by the interaction of IL-22 and IL-22RA to form a cytokine receptor complex with a higher affinity for IL-22 (Li J et al. 2004). Since IL-10RB is broadly expressed by many different cell types, IL-22RA expression is the limiting component that determines IL-22 responsiveness of cells. IL-22RA is expressed strongly in the liver, as well as in the skin, lungs, pancreas and other peripheral tissues (Wolk K et al. 2004; Aggarwal S et al. 2001).
Extensive screening of different cell lines has revealed that only cells which express IL-22RA respond to IL-22, suggesting that there is no alternate receptor that can mediate IL-22 signaling.
A soluble receptor termed IL-22 binding protein (IL-22BP; also known as IL22BP, IL22RA2, IL-22R-alpha2, CRF2X, CRF2—S1 and CRF2-10) is also able to bind to IL-22 as a natural protein antagonist and probably provides systemic regulation of IL-22 activity (Kotenko S V et al. 2003). IL-22 has been found in diseased tissues from patients with different chronic inflammatory diseases that involve infiltrating activated T cells, such as psoriasis, psoriatic arthritis and atopic dermatitis. IL-22 has been most commonly described as a pro-inflammatory cytokine because of its expression in lesions of patients with chronic inflammatory diseases and its induction of pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α (Wolk K et al. 2004; Andoh A et al. 2005; Ikeuchi H et al. 2005; Nograles K E et al. 2009a.; Nograles K E et al. 2009b). Most recently, Zheng et al. showed that IL-22 is important for mediating IL-23-induced dermal inflammation in a mouse model of psoriasis, indicating a pro-inflammatory role (Zheng Y et al. 2007). Given the biological effects of IL-22, including keratinocyte hyperplasia, induction of chemokine and pro-inflammatory cytokine production in certain tissue, the use of antagonists that block, inhibit, reduce or neutralize the activity of IL-22, e.g. by interfering with the receptor binding, may prevent infiltration of pathogenic cells at inflammatory sites. Mouse anti-human IL-22RA monoclonal antibodies have been previously described in PCT patent application WO 2006/047249 filed on Oct. 21, 2005. However, mouse antibodies may cause immunogenicity and humanized anti-human IL-22RA antibodies are desirable. Humanized antibodies generally have at least three potential advantages over mouse antibodies for use in human therapy: (1) because the effector portion is human, it may interact better with the other parts of the human immune system (e.g., destroy the target cells more efficiently by complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)); (2) the human immune system should not recognize the framework or constant region of the humanized antibody as foreign, and therefore the antibody response against such an injected antibody should be less than against a totally foreign mouse antibody; and (3) injected mouse antibodies have been reported to have a half-life in the human circulation much shorter than the half-life of human antibodies. Injected humanized antibodies will presumably have a half-life more similar to naturally occurring human antibodies, allowing smaller and less frequent doses to be given. Thus, in view of the above, there is a need for humanized anti-human IL-22RA antibodies for treating IL-22 mediated inflammation, such as psoriasis, psoriatic arthritis and atopic dermatitis.